4,5α-Epoxy-3-hydroxy or methoxy-7-(1-hydroxy-alkyl or 1-oxoalkyl)morphinan-6-one compounds

ABSTRACT

Disclosed are 4,5α-epoxy-3-hydroxy or methoxy-7-(1-hydroxyalkyl or 1-oxoalkyl)morphinan-6-one compounds characterized by the structural formulae: ##STR1## In the foregoing formulae R is methyl, cyclopropylmethyl, cyclobutylmethyl, propargyl, allyl, dimethylallyl, cis-chloroallyl or furfuryl; R 1  is H or methyl; R 2  is straight or branched chain alkyl of from 1 to 10 carbon atoms, aryl, substituted aryl or arylalkyl, in which the alkyl group contains from 1 to 6 carbon atoms, and R 3  is a straight chain alkyl of 1 to 4 carbon atoms.

BACKGROUND OF THE INVENTION

Certain well known narcotic analgesics belong to the class of4,5α-epoxymorphinan compounds which have the following basic ringsystem, in which the atoms are numbered as indicated. ##STR2##

The two most familiar compounds of this class are morphine and its3-methyl ether, codeine, with the structures indicated below. ##STR3##

When the 6-hydroxyl group of each of these compounds is oxidized to anoxo group, the compounds conveniently are referred to as morphinone andcodeinone, respectively. When the N-methyl groups of the lattercompounds are replaced by other substituent groups they may be referredto as N-substituted normorphinones and norcodeinones, respectively.There are two types of nomenclature commonly used for describingcompounds herein. The trivial names, such as morphine or morphinone, arewidely accepted and used for the sake of brevity and clarity. TheChemical Abstracts nomenclature is preferred and is used whereeverprecision is needed.

Morphine and its relatives are used primarily for the relief of pain(i.e., as analgesics). They are narcotic and possess dependence-inducingability and produce other side effects that make them less than idealanalgesics (emesis, constipation, sweating, respiratory depressions,miosis). A compound with the appropriate profile of analgesic (agonist)and narcotic antagonist actions which is not morphine-like has potentialas an analgesic agent for treatment of moderate to severe pain withoutliability of drug dependence. Furthermore, a compound having only strongnarcotic antagonist action may be a desirable agent for treatment ofdrug dependence.

Bentley and Hardy disclose in Journal of the American Chemical Society,89:13, Pp. 3267-73 certain Diels-Alder adducts of thebaine having theformula: ##STR4## where R is methyl or phenyl. It is stated that thesecompounds possess analgesic activity. The6,14-endoethenotetrahydrothebaine (oripavine) series of analgesics asdisclosed by Bentley and his coworkers differs from the present seriesby the presence of the 6,14-ethenobridge in the oripavines. This bridgealters the stereochemistry of the molecules. Furthermore, the oripavinescontain a methyl ether of a tertiary alcohol at C-6 whereas the presentseries contains a keto group at that position. No specific data on theanalgesic activity of the 7-acyl oripavines are given. The analgesicactivity of the side chain tertiary alcohols in the oripavine seriesgenerally increases through R═C₃ H₇ and then decreases. The morphineantagonist activity for the N--CH₂ --cC₃ H₅ derivatives decreases withthe increase in the size of R.

SUMMARY OF THE INVENTION

The present invention involves 4,5α-epoxy-3-hydroxy ormethoxy-7-(1-hydroxyalkyl or 1-oxoalkyl)morphinan-6-one compoundscharacterized by the structural formulae: ##STR5## In the foregoingformulae R is methyl, cyclopropylmethyl, cyclobutylmethyl, propargyl,allyl, dimethylallyl, cis-chloroallyl, or furfuryl; R₁ is H or methyl;R₂ is straight or branched chain alkyl of from 1 to 10 carbon atoms,aryl, substituted aryl or arylalkyl in which the alkyl chain containsfrom 1 to 6 carbon atoms and R₃ is a straight chain alkyl group of 1 to4 carbon atoms.

DETAILED DESCRIPTION

The preparation of the compounds of the present invention is outlined inScheme I. ##STR6##

Referring to Scheme I, Compound (2) is prepared by reacting Compound (1)[I. Seki, Yagugaku Zasshi 84, 615 (1964) CA: 61:9544 (1964)] where R ismethyl, cyclopropylmethyl, cyclobutylmethyl, propargyl, allyl,dimethylallyl, cis-chloroallyl, furfuryl with an acyl chloride in thepresence of triethylamine followed by treatment with water.

Suitable acyl halides include compounds of the formula: ##STR7## inwhich R₂ is a straight or branched chain alkyl of 1 to 10 carbon atoms,e.g., methyl, ethyl, propyl, isopropyl, pentyl, heptyl or decyl; aryl,e.g., phenyl, naphthyl and heteroaryls including furanyl; or substitutedaryl, e.g., p-fluorophenyl, trimethylphenyl, nitrophenyl andmethoxyphenyl; and arylalkyl, e.g., phenethyl. The reaction is carriedout in a suitable inert solvent, such as benzene, toluene and thehalogenated hydrocarbons chloroform and trichloroethylene with orwithout the addition of an organic base at a temperature in the range offrom 25° C. to 150° C. for a period sufficient to form the desiredintermediate which is converted to Compound (2) by adding water to thereaction medium. Recovery and purification of Compound (2) isaccomplished by treatment with base, followed by extraction andchromatographic purification. Compound (2) is converted to Compound (3)(its 3-hydroxy counterpart) by reaction with boron tribromide in asuitable inert solvent at room temperature. The compounds of Formula 2and 3 are important in that they can be converted to the tertiaryalcohol 4 by the addition of an alkyl lithium reagent of the formula R₃Li where R₃ is a straight chain alkyl group of 1 to 4 carbon atoms. Thisreaction is carried out in a suitable solvent such as tetrahydrofuran,diethyl ether or dimethoxyethane at a temperature of from -90° to +25°C. We have found temperatures on the order of -78° C. to be preferable.

Certain of the compounds corresponding to Formulae 2, 3 and 4 have beenfound to have analgesic activity, narcotic antagonist activity or acombination of these activities which render them useful as nonaddictivestrong analgesics.

The preparation of the morphinan compounds of the present invention isfurther illustrated by the following examples.

EXAMPLE I Preparation of 7-(4-Phenylbutyroyl)Dihydrocodeinone ##STR8##To a cooled solution of 6 g. of the morpholine enamine ofdihydrocodeinone (1) in 5.6 g. of dry triethylamine and 350 ml. oftrichloroethylene was slowly added 10.04 g. of 4-phenylbutyroyl chloridein 50 ml. of trichloroethylene. After 1.5 hr. the ice bath was replacedwith a heating bath and the solution was refluxed for 8.5 hr. thenallowed to stir at room temperature overnight.

After addition of 100 ml. of water the mixture was refluxed for 2 hr.After cooling, the mixture was basified with concentrated ammoniumhydroxide whereupon the aqueous phase was separated and extracted twicewith chloroform. The combined organic layers were dried (Na₂ SO₄) andconcentrated in vacuo. The residue was dissolved in methanol, andstirred with about 10 g. of solid potassium carbonate for 5.5 hr. Thesolution was filtered and concentrated in vacuo and the residuepartitioned between diethyl ether and water. The aqueous layer wasextracted three times with diethyl ether at which point the combinedether layers were dried (Na₂ SO₄) and concentrated to afford 14.2 g. ofan oil. Chromatography of this oil on 300 g. of silica gel afforded 3.40g. (49% yield) of 7-(4-phenylbutyroyl)dihydrocodeinone (2) upon elutionwith graded methanol-chloroform mixtures. Recrystallization from ethanolafforded a solid melting at 170°-171.5° C.

Anal. Calc. for C₂₀ H₃ NO₄ : C, 75.48; H, 7.01; N, 3.14. Found: C,75.46; H, 7.08; N, 3.12.

Mass Spec. (m/e) 445 (M+).

EXAMPLE II Preparation of 7-(4-Phenylbutyroyl)Dihydromorphone ##STR9##To a solution of 8.9 ml. of boron tribromide in 150 ml. of chloroformwas added, dropwise, a solution of 3.4 g.7-(4-phenylbutyroyl)dihydrocodeinone (2) in 100 ml. of chloroform. Afterstirring for one additional hour, the reaction mixture was quenched bypouring it into a stirred mixture of ice and concentrated ammoniumhydroxide (1:1). After stirring for 1 hr. the aqueous layer wasseparated and extracted twice with chloroform. The combined chloroformlayers were dried (Na₂ SO₄) and concentrated in vacuo to afford 3.5 g.of a gummy solid. This material was chromatographed on 90 g. of silicagel. Elution with graded methanol-chloroform mixtures afforded 2.19 g.(65% yield) of 7-(4-phenylbutyroyl)dihydrobromorphone (3).

The material forms a hydrochloride salt which decomposes at 175° C.

Mass spec. (m/e) 431 (M⁺ ; free base).

EXAMPLE III Preparation of17-Cyclopropylmethyl-4,5α-Epoxy-3-Hydroxy-7-(1-Hydroxy-1-Methylbutyl)Morphinan-6-One##STR10## To 375 mg. of17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-7-butanoylmorphinan-6-one (4)in 10 ml. of dry tetrahydrofuran at -78° C. was added, dropwise, 6 ml.of 1.6 M methyl lithium. The mixture was then allowed to warm slowly(over 2 hr.) to -55° C. The mixture was then quenched by the sequentialaddition of moist diethyl ether and saturated aqueous ammonium chloride.After acidification with acetic acid and rebasification with ammoniumhydroxide the aqueous solution was extracted with chloroform. Theorganic layer was dried (Na₂ SO₄) and concentrated to afford 362 mg. ofcrude oil. Chromatography on 8 g. of silica gel with gradedmethanol-chloroform mixtures afforded a fraction rich in (5) which waspurified further by preparative tlc to afford 121 mg. (29%) of17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-7-(1-hydroxy-1-methylbutyl)morphinan-6-oneas a glassy foam.

Mass spec. (m/e) 411 (M⁺); 393 (M⁺ -18).

Other compounds within the scope of the present invention are preparedby the procedure of the examples using the appropriate startingmaterials. The physical characteristics of these compounds, whosestructures can be determined by reference to Tables I and II, supra, areset out in the following table.

    __________________________________________________________________________    PHYSICAL DATA ON COMPOUNDS OF THIS INVENTION                                  Free Base                                                                                 Mass                 Analysis                                     Com-                                                                              mp      spec M+                                                                             FORMULA        Calculated  Found       HCl salt             pound                                                                             (°C.)                                                                      MW  (m/e) (free base or HCl salt)                                                                      C   H  N    C    H  N   mp(°C.)       __________________________________________________________________________    TR                                                                            5463                                                                              164-5                                                                             381       C.sub.23 H.sub.27 NO.sub.4                                                                   72.42                                                                             7.13                                                                             3.61 72.34                                                                              7.14                                                                             3.67                     TR                                                                            5475                                                                              135 367 367   C.sub.22 H.sub.25 NO.sub.4.0.5CH.sub.3 OH                                                    70.46                                                                             7.11                                                                             3.65 70.92                                                                              6.92                                                                             3.72                     TR                                                                            5570    395 395   C.sub.24 H.sub.29 NO.sub.4.HCl.2H.sub.2 O                                                    61.50                                                                             7.33                                                                             2.97 60.86                                                                              6.53                                                                             2.96                                                                              170(dec)             TR                                                                            5573    381       C.sub.23 H.sub.27 NO.sub.4.HCl.2H.sub.2 O                                                    60.84                                                                             7.12                                                                             3.08 59.71                                                                              6.42                                                                             3.05                                                                              215(dec)             TR                                                                            5464    409       C.sub.25 H.sub.31 NO.sub.4.HCl.H.sub.2 O                                                     64.71                                                                             7.39                                                                             3.02 64.81                                                                              7.00                                                                             3.04                                                                              155                  TR                                                                            5476    393       C.sub.24 H.sub.29 NO.sub.4.HCl.H.sub.2 O                                                     64.05                                                                             7.18                                                                             3.11 64.01                                                                              7.20                                                                             3.09                     TR                                                                            5519    423       C.sub.26 H.sub.33 NO.sub.4.HCl.0.5H.sub.2 O                                                  66.56                                                                             7.52                                                                             2.99 66.41                                                                              7.55                                                                             2.99                     TR                                                                            5520    409       C.sub.25 H.sub.31 NO.sub.4.HCl                                                               67.33                                                                             7.23                                                                             3.14 67.13                                                                              7.30                                                                             3.13                                                                              >240                 TR                                                                            5504    437       C.sub.27 H.sub.35 NO.sub.4.HCl.H.sub.2 O                                                     65.89                                                                             7.80                                                                             2.85 66.04                                                                              7.43                                                                             2.86                                                                              135                  TR                                                                            5505    423       C.sub.26 H.sub.33 NO.sub.4.HCl.H.sub.2 O                                                     65.32                                                                             7.61                                                                             2.93 65.26                                                                              7.59                                                                             2.91                                                                              190(dec)             TR                                                                            5539    451       C.sub.28 H.sub.37 NO.sub.4.HCl.0.5H.sub.2 O                                                  67.64                                                                             7.92                                                                             2.82 68.09                                                                              7.79                                                                             2.81                     TR                                                                            5540    437 437   C.sub.27 H.sub.35 NO.sub.4.HCl.0.5H.sub.2 O                                                  67.13                                                                             7.72                                                                             2.90 67.08                                                                              7.75                                                                             2.90                                                                              175                  TR                                                                            5509    409 409   C.sub.25 H.sub.31 NO.sub.4.HCl.H.sub.2 O                                                     64.70                                                                             7.40                                                                             3.02 67.86                                                                              6.89                                                                             2.92                                                                              190(dec)             TR                                                                            5511    395 395   C.sub.24 H.sub.29 NO.sub.4.HCl.H.sub.2 O                                                     64.05                                                                             7.18                                                                             3.11 62.64                                                                              6.78                                                                             2.95                     TR                                                                            5571    437       C.sub.27 H.sub.35 NO.sub.4.HCl.H.sub.2 O                                                     65.90                                                                             7.78                                                                             2.84 65.84                                                                              7.25                                                                             2.94                                                                              170(dec)             TR                                                                            5574    423       C.sub.26 H.sub.33 NO.sub.4.HCl.H.sub.2 O                                                     65.32                                                                             7.59                                                                             2.93 65.29                                                                              7.60                                                                             2.93                                                                              213-5                TR                                                                            5577    457 457   C.sub.29 H.sub.31 NO.sub.4.HCl                                                               70.50                                                                             6.53                                                                             2.84 69.22                                                                              6.18                                                                             2.40                                                                              167-70                                 (contains some pyrone)                                      TR                                                                            5506    429 429   C.sub.27 H.sub.27 NO.sub.4.HCl                              TR                                                                            5501    443 443   C.sub.28 H.sub.29 NO.sub.4.HCl.H.sub.2 O                                                     66.45                                                                             6.19                                                                             2.77 67.53                                                                              6.30                                                                             3.72                                                                              140                  TR                                                                            5579                                                                              155-7                                                                             447       C.sub.27 H.sub.26 FNO.sub.4                                                                  72.47                                                                             5.96                                                                             3.13 72.37                                                                              5.88                                                                             3.10                     TR                                                                            5575    461 461   C.sub.28 H.sub.28 FNO.sub.4.HCl.H.sub.2 O                                                    65.16                                                                             6.07                                                                             2.71 64.53                                                                              5.76                                                                             2.67                                                                              178-80               TR  (dec)                                                                     5649                                                                              145 428       C.sub.25 H.sub.25 NO.sub.5.0.5H.sub.2 O                                                      70.07                                                                             6.12                                                                             3.27 70.11                                                                              6.18                                                                             3.27                     TR                                                                            5634    433       C.sub.26 H.sub.27 NO.sub.5.HCl.1.5H.sub.2 O                                                  62.83                                                                             6.29                                                                             2.82 62.86                                                                              6.32                                                                             2.82                                                                              186-8                MLS                                                                           5695H   355 355   C.sub.21 H.sub.25 NO.sub.4.HCl.H.sub.2 O                                                     61.53                                                                             6.89                                                                             3.41 61.30                                                                              6.88                                                                             3.41                     MLS                                                                           5689H   383 383   C.sub.23 H.sub.29 NO.sub.4 .HCl--0.6CHCl.sub.3                                               57.65                                                                             6.28                                                                             2.85 57.61                                                                              6.50                                                                             3.05                                                                              160(dec)             MLS                                                                           5690H   417 417   C.sub.26 H.sub.27 NO.sub.4.HCl--0.5CHCl.sub.3                                                61.96                                                                             5.60                                                                             2.73 61.39                                                                              5.77                                                                             2.85                                                                              175(dec)             MLS                                                                           5691H   431 431   C.sub.27 H.sub.24 NO.sub.4.HCl.0.7CHCl.sub.3                                                 60.31                                                                             5.62                                                                             2.54 60.41                                                                              5.93                                                                             2.66                                                                              175(dec)             MLS                                                                           5692                                                                              160-1.5                                                                           369 369   C.sub.22 H.sub.27 NO.sub.4.0.25H.sub.2 O                                                     70.56                                                                             7.53                                                                             3.74 70.60                                                                              7.64                                                                             3.88                     MLS                                                                           5682                                                                              155-6                                                                             397       C.sub.24 H.sub.31 NO.sub.4                                                                   72.51                                                                             7.86                                                                             3.52 72.44                                                                              7.86                                                                             3.52                     MLS                                                                           5683                                                                              170-1.5                                                                           445       C.sub.28 H.sub.31 NO.sub.4                                                                   75.48                                                                             7.01                                                                             3.14 75.46                                                                              7.08                                                                             3.12                     MLS                                                                           5688H   431 431   C.sub.27 H.sub.29 NO.sub.4.HCl.H.sub.2 O                                                     66.71                                                                             6.65                                                                             2.88 67.30                                                                              6.71                                                                             2.91                                                                              (125(dec)            TR                                                                            5492                                                                              oil 357 357   C.sub.21 H.sub.27 NO.sub.4                                  TR                                                                            5479                                                                              oil 397 397   C.sub.24 H.sub.31 NO.sub.4                                  TR                                                                            5499                                                                              foam                                                                              425 425   C.sub.26 H.sub.35 NO.sub.4.0.2CHCl.sub.3                                                     70.20                                                                             7.90                                                                             3.12 70.14                                                                              7.81                                                                             3.28                     TR                                                                            5544                                                                              foam                                                                              439 439   C.sub.27 H.sub.37 NO.sub.4                                                                   73.76                                                                             8.50                                                                             3.19 72.83                                                                              8.35                                                                             3.06                     TR                                                                            5543                                                                              foam                                                                              411 411   C.sub.25 H.sub.33 NO.sub.4.0.3CHCl.sub.3                                                     67.90                                                                             7.51                                                                             3.13 67.84                                                                              7.54                                                                             3.17                     TR                                                                            5551                                                                              134-7                                                                             425 425   C.sub.26 H.sub.35 NO.sub.4                                                                   73.38                                                                             8.29                                                                             3.29 71.47                                                                              7.37                                                                             3.79                                                          (reverse aldol on heating)               TR                                                                            5538                                                                              foam                                                                              439 439   C.sub.27 H.sub.27 NO.sub.4.0.1CHCl.sub.3                                                     72.07                                                                             8.30                                                                             3.10 72.43                                                                              8.29                                                                             3.27                     TR                                                                            5572                                                                              195-7                                                                             411 411   C.sub.25 H.sub.33 NO.sub.4.0.4CHCl.sub.3                                                     66.40                                                                             7.34                                                                             3.05 65.77                                                                              7.52                                                                             2.45                     MLS                                                                           5694                                                                              194-5                                                                             399 399   C.sub.24 H.sub.33 NO.sub.4                                                                   72.15                                                                             8.33                                                                             3.51 72.04                                                                              8.33                                                                             3.47                     __________________________________________________________________________

PHARMACOLOGICAL EVALUATION

The compounds whose preparation is disclosed in the foregoing exampleswere screened to determine the following biological activities:

(A) Analgesic effects upon mice (acetic acid writhing test).

(B) Narcotic antagonist activity in rats (modified rat tail flick test).

TEST A. ACETIC ACID MOUSE WRITHING TEST

The analgesic effects of test compounds were determined in mice by useof the acetic acid writhing test described by B. A. Whittle, Brit. J.Pharmacol., 22:246 (1964). In this test at least three groups of fivemale CD-1 mice each were given subcutaneous doses of the test drugdissolved in either distilled water or distilled water acidified withHCl depending on the solubility of the compound. Fifteen (15) minutespost drug, 0.4 milliliter of a 0.75% or 1.0% or 0.6 milliliter of a 1.0%V/V acetic acid in distilled water solution was administeredintraperitoneally. The number of writhes in a 20 minute intervalbeginning 5 minutes after the acetic acid injection were determined andcompared with the number of writhes in control groups which had receivedonly acetic acid.

Percent inhibition of writhing was calculated as: ##EQU1##

The ED₅₀ dose, i.e., the dose required to reduce the number of writhesby 50%, was determined graphically from a plot of % inhibition as aprobit versus log dose. Confidence limits of 95% were calculated on thebasis of those results falling in the range 16-84% inhibition. SeeLitchfield, J. T. and Wilcoxon, F., J. Pharmacol. Exp. Ther., 96:99,(1949).

TEST B. EVALUATION OF NARCOTIC ANTAGONIST

The narcotic antagonist effects of test compounds were determined by amodification of the rat tail flick procedure of Harris and Pierson, J.Pharmacol. Exp. Ther. 143:141 (1964).

Male albino Wistar rats (100-120 g.) were used for this study. A rat'stail is so placed so as to cover a photocell. Heat is applied by a lampin a reflector with a timer being connected to the lamp and photocell sothat the timer goes on when the light is turned on and is turned offwhen the photocell is uncovered. A rheostat, incorporated into a heatinglamp is used to adjust the intensity of the light falling on the tail ofthe rat such that the rat's control reaction time is from 1.2 to 5.8seconds. Animals with a control reaction time outside this range arerejected. The rheostat adjustment is made only if a significantproportion (more than 1 out of every 10 rats) of the reaction times areoutside the range of 1.2 to 5.8 seconds. Groups of five rats were usedeach time, and two control times were determined at least 30 minutesapart.

The test drug was given intraperitoneally and this was followed tenminutes later by an ED₈₀ dose of morphine subcutaneously. The animalswere retested at 20 minutes after the morphine injection. Controlanimals were given morphine only. A ten second cutoff time is employed;if the rat does not flick its tail in 10 seconds it is is removed fromthe heat source. The data were calculated as follows: ##EQU2##

The data were plotted on log-probit paper and AD₅₀ values, i.e., thedose required to inhibit the morphine effect by 50% within 95%confidence limits, were determined by the method of Litchfield andWilcoxon.

The 4,5α-epoxy-3-hydroxy or methoxy-7-(1-hydroxyalkyl)morphinan-6-onedata is tabulated in Table I whereas Table II sets out the data for the1-hydroxyalkyl compounds. In the following tables CPM means"cyclopropylmethyl", NDR means "no dose response" and the designation X%(Y) means that the number of writhes were reduced by X% at a dosage of Ymg/kg.

                  TABLE I                                                         ______________________________________                                         ##STR11##                                                                                                   ED.sub.50                                                                            AD.sub.50                               Compound RR.sub.1  R.sub.2     (mg/kg)                                                                              (mg/kg)                                 ______________________________________                                        TR-5463  CPMCH.sub.3                                                                             CH.sub.3    9%(10) Ia(10)                                  TR-5475  CPMH      CH.sub.3    4.05   1.3                                     TR-5570  CPMCH.sub.3                                                                             C.sub.2 H.sub.5                                                                           11%(10)                                                                              6.5                                     TR-5573  CPMH      C.sub.2 H.sub.5                                                                           Ia(10) 0.51                                    TR-5464  CPMCH.sub.3                                                                             C.sub.3 H.sub.7                                                                           2.81   8.1                                     TR-5476  CPMH      C.sub.3 H.sub.7                                                                           4.65   2.55                                    TR-5519  CPMCH.sub.3                                                                             C.sub.4 H.sub.9                                                                           >10.0  Ia(10)                                  TR-5520  CPMH      C.sub.4 H.sub.9                                                                           1.59   77%(10)                                 TR-5504  CPMCH.sub.3                                                                             C.sub.5 H.sub.11                                                                          5.7    Ia(10)                                  TR-5505  CPMH      C.sub.5 H.sub.11                                                                          0.29   22                                      TR-5539  CPMCH.sub.3                                                                             C.sub.6 H.sub.13                                                                          >10.0  >10.0                                   TR-5540  CPMH      C.sub.6 H.sub.13                                                                          0.4    Ia(10)                                  TR-5509  CPMCH.sub.3                                                                             i-C.sub.3 H.sub.7                                                                         7.5    2.8                                     TR-5511  CPMH      i-C.sub. 3 H.sub.7                                                                        >10    0.81                                    TR-5571  CPMCH.sub.3                                                                             t-C.sub.4 H.sub.9                                                                         Ia(10) 13%(10)                                 TR-5574  CPMH      CH.sub.2 t-C.sub.4 H.sub.9                                                                Ia(10) >10                                     TR-5577  CPMCH.sub.3                                                                             CH.sub.2 C.sub.6 H.sub.5                                                                  21%(10)                                                                              Ia(10)                                  TR-5506  CPMH      C.sub.6 H.sub.5                                                                           4.35   0.24                                    TR-5501  CPMCH.sub.3                                                                             C.sub.6 H.sub.5                                                                           11.3   8.0                                     TR-5579  CPMH      C.sub.6 H.sub.4pF                                                                         29%(10)                                                                              45%(10)                                 TR-5575  CPMCH.sub.3                                                                             C.sub.6 H.sub.4pF                                                                         Ia(10) 17%(10)                                 TR-5649  CPMH      C.sub.4 H.sub.3 O                                                                         28%(10)                                                                              NDR                                     TR-5634  CPMCH.sub.3                                                                             C.sub.4 H.sub.3 O                                                                         14%(10)                                                                              3.95                                    MLS-5692 CH.sub.3 CH.sub.3                                                                       C.sub.3 H.sub.7                                                                           Ia(10) --                                      MLS-5695 CH.sub.3 H                                                                              C.sub.3 H.sub.7                                                                           5.25   --                                      MLS-5682 CH.sub.3 CH.sub.3                                                                       C.sub.5 H.sub.11                                                                          4.0    --                                      MLS-5689 CH.sub.3 H                                                                              C.sub.5 H.sub.11                                                                          0.76   --                                      MLS-5688H                                                                              CH.sub.3 CH.sub.3                                                                       (CH.sub.2).sub.2C.sub.6 H.sub.5                                                           0.62   --                                      MLS-5690 CH.sub.3 H                                                                              (CH.sub.2).sub.2C.sub.6 H.sub.5                                                           0.105  --                                      MLS-5683 CH.sub.3 CH.sub.3                                                                       (CH.sub.2).sub.3C.sub.6 H.sub.5                                                           0.41   --                                      MLS-5691 CH.sub.3 H                                                                              (CH.sub.2 ).sub.3C.sub.6 H.sub.5                                                          0.0052 --                                      ______________________________________                                    

                  TABLE II                                                        ______________________________________                                         ##STR12##                                                                                                       ED.sub.50                                                                            AD.sub.50                           Compound                                                                              R       R.sub.1                                                                              R.sub.3                                                                             R.sub.2                                                                             (mg/kg)                                                                              (mg/kg)                             ______________________________________                                        TR-5492 CH.sub.3                                                                              CH.sub.3                                                                             CH.sub.3                                                                            CH.sub.3                                                                            4.5    --                                  TR-5479 CPM     CH.sub.3                                                                             CH.sub.3                                                                            CH.sub.3                                                                            Ia(10) 41%(10)                             TR-5499 CPM     CH.sub.3                                                                             CH.sub.3                                                                            C.sub.3 H.sub.7                                                                     0.42   12%(7)                              TR-5544 CPM     CH.sub.3                                                                             CH.sub.3                                                                            C.sub.4 H.sub.9                                                                     10%(10)                                                                              Ia(10)                              TR-5543 CPM     H      CH.sub.3                                                                            C.sub.3 H.sub.7                                                                     1.8    2.8                                 TR-5551 CPM     H      CH.sub.3                                                                            C.sub.4 H.sub.9                                                                     40%(10)                                                                              2.5                                 TR-5538 CPM     H      CH.sub.3                                                                            C.sub.5 H.sub.11                                                                    0.28   6.6                                 TR-5572 CPM     H      CH.sub.3                                                                            i-C.sub.3 H.sub.7                                                                   7.8    2.2                                 MLS-5694                                                                              CH.sub.3                                                                              H      C.sub.5 H.sub.11                                                                    CH.sub.3                                                                            2.9    --                                  ______________________________________                                    

What is claimed is:
 1. 4,5α-epoxy-3-hydroxy or methoxy-7-(1-hydroxyalkylor 1-oxoalkyl)morphinan-6-one compounds characterized by the structuralformulae: ##STR13## wherein R is methyl, cyclopropylmethyl,cyclobutylmethyl, propargyl, allyl, dimethylallyl, cis-chloroallyl orfurfuryl; R₁ is H or methyl; R₂ is straight or branched chain alkyl offrom 1 to 10 carbon atoms, phenyl or phenylalkyl in which the alkylchain contains from 1 to 6 carbon atoms, and R₃ is a straight chainalkyl of 1 to 4 carbon atoms.
 2. The compounds of claim 1 which arecharacterized by the formula: ##STR14## wherein R, R₁ and R₂ are aspreviously defined.
 3. A compound as defined by claim 2 wherein R iscyclopropylmethyl, R₁ is H and R₂ is CH₃.
 4. A compound as defined byclaim 2 wherein R is cyclopropylmethyl, R₁ is CH₃ and R₂ is C₃ H₇.
 5. Acompound as defined by claim 2 wherein R is cyclopropylmethyl, R₁ is Hand R₂ is C₃ H₇.
 6. A compound as defined by claim 2 wherein R iscyclopropylmethyl, R₁ is CH₃ and R₂ is i-C₃ H₇.
 7. A compound as definedby claim 2 wherein R is cyclopropylmethyl, R₁ is H and R₂ is C₆ H₅.
 8. Acompound as defined by claim 2 wherein R is cyclopropylmethyl, R₁ is CH₃and R₂ is C₆ H₅.
 9. A compound as defined by claim 2 wherein R iscyclopropylmethyl, R₁ is H and R₂ is C₂ H₅.
 10. A compound as defined byclaim 2 wherein R is cyclopropylmethyl, R₁ is H and R₂ is C₄ H₉.
 11. Acompound as defined by claim 2 wherein R is cyclopropylmethyl, R₁ is Hand R₂ is C₅ H₁₁.
 12. A compound as defined in claim 2 wherein R iscyclopropylmethyl, R₁ is H and R₂ is C₆ H₁₃.
 13. A compound as definedin claim 2 wherein R is cyclopropylmethyl, R₁ is H and R₂ is i-C₃ H₇.14. A compound as defined in claim 2 wherein R is CH₃, R₁ is H and R₂ isC₅ H₁₁.
 15. A compound as defined in claim 2 wherein R is CH₃, R₁ is CH₃and R₂ is (CH₂)₂ --C₆ H₅.
 16. A compound as defined in claim 2 wherein Ris CH₃, R₁ is H and R₂ is (CH₂)₂ --C₆ H₅.
 17. A compound as defined inclaim 2 wherein R is CH₃, R₁ is CH₃ and R₂ is (CH₂)₃ --C₆ H₅.
 18. Acompound as defined in claim 2 wherein R is CH₃, R₁ is H and R₂ is(CH₂)₃ --C₆ H₅.
 19. The compounds of claim 1 which are characterized bythe formula: ##STR15## wherein R, R₁, R₂ and R₃ are as previouslydefined.
 20. A compound as defined by claim 19 wherein R iscyclopropylmethyl, R₁ is H, R₂ is C₃ H₇ and R₃ is CH₃.
 21. A compound asdefined by claim 19 wherein R is cyclopropylmethyl, R₁ is H, R₂ is C₅H₁₁ and R₃ is CH₃.
 22. A compound as defined by claim 19 wherein R iscyclopropylmethyl, R₁ is H, R₂ is i-C₃ H₇ and R₃ is CH₃.
 23. A compoundas defined by claim 19 wherein R₁ is cyclopropylmethyl, R₁ is CH₃, R₂ isC₃ H₇ and R₃ is CH₃.